Animal models of Huntington's disease

Huntington's disease (HD) is a neurological disorder caused by a genetic mutation in the IT15 gene. Progressive cell death in the striatum and cortex, and accompanying declines in cognitive, motor, and psychiatric functions, are characteristic of the disease. Animal models of HD have provided insight into disease pathology and the outcomes of therapeutic strategies. Earlier studies of HD most often used toxin-induced models to study mitochondrial impairment and excitotoxicity-induced cell death, which are both mechanisms of degeneration seen in the HD brain. These models, based on 3-nitropropionic acid and quinolinic acid, respectively, are still often used in HD studies. The discovery in 1993 of the huntingtin mutation led to the creation of newer models that incorporate a similar genetic defect. These models, which include transgenic and knock-in rodents, are more representative of the HD progression and pathology. An even more recent model that uses a viral vector to encode the gene mutation in specific areas of the brain may be useful in nonhuman primates, as it is difficult to produce genetic models in these species. This article examines the aforementioned models and describes their use in HD research, including aspects of the creation, delivery, pathology, and tested therapies for each model.     

Lessons from animal models of Huntington's disease

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HD gene. The expanded repeats are translated into an abnormally long polyglutamine tract close to the N-terminus of the HD gene product, huntingtin. Studies in mouse models and human suggest that the mutation is associated with a deleterious gain of function. There is now a wide range of mouse models for HD, providing important insights into processes associated with disease pathogenesis. These models have been complemented by studies in Drosophila and Caenorhabditis elegans that have allowed the identification of possible modifier loci through suppressor screens.     

Transgenic animal models of cardiovascular disease

Transgenic experimentation has become a crucial part of hypertension and atherosclerosis research, and is growing more important in several other areas of cardiovascular disease. It has recently made a particular contribution to understanding the role of the renin-angiotensin system in controlling hypertension. The study of blood pressure regulation, cardiac hypertrophy, atherogenesis and thrombosis are also benefiting from the transgenic approach.     

Transgenic mouse models of Alzheimer's disease

Recent advances in the understanding of the genetic basis of Alzheimer's disease have enabled the production of transgenic mouse models of the disease. Utilizing both cDNA- and genomic-based approaches, these mouse models for Alzheimer's disease have already provided valuable insights into the pathogenesis of the disease and potential therapeutic interventions.     

Transgenic animals in inflammatory disease models

Inflammatory diseases affect a significant portion of the population worldwide and have been intensely studied for several decades. The advent of transgenic technology has allowed researchers to study individual gene contributions to the pathogenesis of these diseases. This has been done using standard inflammatory disease models in transgenic animals and by identifying novel models through the spontaneous generation of disease in the transgenic animal. Recent advances have been made in the understanding of rheumatoid arthritis, pulmonary inflammation, multiple sclerosis and inflammatory bowel disease through the use of transgenic animals in models of human inflammatory disease.     

Transgenic models for cytokine-induced neurological disease

Considerable evidence supports the idea that cytokines are important mediators of pathophysiologic processes within the central nervous system (CNS). Numerous studies have documented the increased production of various cytokines in the human CNS in a variety of neurological and neuropsychiatric disorders. Deciphering cytokine actions in the intact CNS has important implications for our understanding of the pathogenesis and treatment of these disorders. One approach to address this problem that has been used widely employs transgenic mice with CNS-targeted production of different cytokines. Transgenic production of cytokines in the CNS of mice allows not only for the investigation of complex cellular responses at a localized level in the intact brain but also more closely recapitulates the expression of these mediators as found in disease states. As discussed in this review, the findings show that these transgenic animals exhibit wide-ranging structural and functional deficits that are linked to the development of distinct neuroinflammatory responses which are relatively specific for each cytokine. These cytokine-induced alterations often recapitulate those found in various human neurological disorders not only underscoring the relevance of these models but also reinforcing the clinicopathogenetic significance of cytokines in diseases of the CNS.     

喹啉酸所致亨廷顿病动物模型

亨廷顿病(Huntington’s disease,HD)是以不自主舞蹈样动作、进行性认知障碍,痴呆为特征的一种常见染色体显性遗传病。兴奋性毒性作用是目前公认的HD发病机制之一,其中喹啉酸(quinolinic acid,QA)作为神经兴奋性毒素,可以损伤相应神经元,导致大脑功能障碍,从而可有效模拟HD的相关改变。本文将就QA动物模型在模拟HD时的优缺点和目前QA在药物研究、疾病治疗等不同方面的应用进行综述。     

Transgenic animals as models for human disease

Transgenic animals, especially mice, have been used quite extensively as models for various human diseases. At first, the level of scientific inquiry was driven by the need to establish the model. In many cases, these models may be considered quite crude because of their limitations. More recently, transgenic models of disease have become more refined and are currently being used to study the pathological mechanisms behind the disease rather than to just provide a model of the disease. Using some examples from the recent literature, we will document the current level and complexity of inquiry using transgenic animals. New techniques and techniques that may prove promising will be discussed. This revised version was published online in August 2006 with corrections to the Cover Date.     

Ku70 alleviates neurodegeneration in Drosophila models of Huntington's disease

DNA damage accumulates in genome DNA during the long life of neurons, thus DNA damage repair is indispensable to keep normal functions of neurons. We previously reported that Ku70, a critical molecule for DNA double strand break (DSB) repair, is involved in the pathology of Huntington's disease (HD). Mutant huntingtin (Htt) impaired Ku70 function via direct interaction, and Ku70 supplementation recovered phenotypes of a mouse HD model. In this study, we generate multiple Drosophila HD models that express mutant huntingtin (Htt) in eye or motor neuron by different drivers and show various phenotypes. In such fly models, Ku70 co-expression recovers lifespan, locomotive activity and eye degeneration. In contrast, Ku70 reduction by heterozygous null mutation or siRNA-mediated knock down accelerates lifespan shortening and locomotion disability. These results collectively support that Ku70 is a critical mediator of the HD pathology and a candidate therapeutic target in HD.     

Choosing and using Drosophila models to characterize modifiers of Huntington's disease

HD (Huntington's disease) is a fatal inherited gain-of-function disorder caused by a polyQ (polyglutamine) expansion in the htt (huntingtin protein). Expression of mutant htt in model organisms is sufficient to recapitulate many of the cellular defects found in HD patients. Many groups have independently developed Drosophila models of HD, taking advantage of its rapid life cycle, carefully annotated genome and well-established molecular toolkits. Furthermore, unlike simpler models, Drosophila have a complex nervous system, displaying a range of carefully co-ordinated behaviours which offer an exquisitely sensitive readout of neuronal disruption. Measuring HD-associated changes in behaviour in Drosophila therefore offers a window into the earliest stages of HD, when therapeutic interventions might be particularly effective. The present review describes a number of recently developed Drosophila models of HD and offers practical guidance on the advantages and disadvantages of various experimental approaches that can be used to screen these models for modifiers of mutant htt-mediated toxicity.     

Mouse models of Huntington's disease and methodological considerations for therapeutic trials

Huntington's disease (HD) is an autosomal dominant, progressive, and fatal neurodegenerative disorder caused by an expanded polyglutamine cytosine–adenine–guanine repeat in the gene coding for the protein huntingtin. Despite great progress, a direct causative pathway from the HD gene mutation to neuronal dysfunction and death has not yet been established. One important advance in understanding the pathogenic mechanisms of this disease has been the development of multiple murine models that replicate many of the clinical, neuropathological, and molecular events in HD patients. These models have played an important role in providing accurate and experimentally accessible systems to study multiple aspects of disease pathogenesis and to test potential therapeutic treatment strategies. Understanding how disease processes interrelate has become important in identifying a pharmacotherapy in HD and in the design of clinical trials. A review of the current state of HD mouse models and their successes in elucidating disease pathogenesis are discussed. There is no clinically proven treatment for HD that can halt or ameliorate the inexorable disease progression. As such, a guide to assessing studies in mouse models and salient issues related to translation from mice to humans are included.     

Huntington's disease

Early in 1993, an unstable, expanded trinucleotide repeat in a novel gene of unknown function was identified on HD chromosomes. This discovery unleased a flurry of experimentation that has established the expanded CAG repeat at the almost universal cause of the characteristic neurologic symptoms and pathology of this neurodegenerative disorder of midlife onset. The biochemical basis for the specific neuronal loss of HD remains uncertain, but the genetic lesion probably acts via its consequent polyglutamine segment in the protein product, huntingtin. This review will describe the basic parameters of the HD repeat's behavior and the knowledge that has accumulated concerning its potential mechanisms of action.